Incident Lupus Nephritis Research Articles

Performance of Modified ALMS and BLISS Criteria with Standard of Care Treatment in Two US Health Care Systems.

A retrospective cohort study was undertaken in a predominantly Black population undergoing standard treatment for lupus nephritis (LN) to estimate the incidence of, and risk factors for, complete response (CR) according to modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Study in Lupus Nephritis (mBLISS) criteria by 12 months. Patients with biopsy-proven LN class III or IV ± V, urine protein-to-creatinine ratio of ≥1gm/gm and estimated glomerular filtration rate of >50 ml/minute/1.73 m2 at the time of the incident LN flare were included. The clinical, treatment, and laboratory factors associated with CR were identified using multivariable Cox regression. Of 173 patients, 86.1% were women, 77.5% were Black, and over half (59.5%) had non-commercial insurance. By 12 months, 20.6% (95% confidence interval (95% CI) 14.6-28.6%) achieved mALMS CR and 33.7% (95% CI 26.4-42.4%) achieved mBLISS CR. Factors associated with mBLISS CR were commercial insurance (adjusted CR ratio=3.5 [95% CI 1.9-6.7]; P < 0.001), albumin (adjusted CR ratio=1.8 per 1 gm/dl increase in albumin; P=0.02), and low C4 (adjusted CR ratio=2.6; P=0.03). Cumulative incidence of end-stage renal disease (ESRD) at 3 years was 23.1% (95% CI 15.7-31.3%) and 6.1% (95% CI 2.8-11.1%) for death. Patients with non-commercial insurance were more likely to develop ESRD, with cumulative incidence of 30.4% (95% CI 19.6-41.9%) compared to 12.7% (95% CI 5.0-24.2%) for patients with commercial insurance (P=0.024). In a primarily Black, uninsured LN population, despite achieving similar CR rates at 12 months, the incidence of ESRD and death exceeded those observed in controlled clinical trials with placebo arms.

Incidence, Prevalence, and Mortality of Lupus Nephritis: A Population-Based Study Over Four Decades Using the Lupus Midwest Network.

There is a paucity of population-based studies investigating the epidemiology of lupus nephritis (LN) in the US and long-term secular trends of the disease and its outcomes. We aimed to examine the epidemiology of LN in a well-defined 8-county region in the US. Patients with incident LN between 1976 and 2018 in Olmsted County, Minnesota (1976-2009) and an 8-county region in southeast Minnesota (2010-2018) were identified. Age- and sex-specific incidence rates and point prevalence over 4 decades, adjusted to the projected 2000 US population, were determined. Standardized mortality ratios (SMRs), survival rates, and time to end-stage renal disease (ESRD) were estimated. There were 72 patients with incident LN between 1976 and 2018, of whom 76% were female and 69% were non-Hispanic White. Mean ± SD age at diagnosis was 38.4 ± 16.24 years. Average annual LN incidence per 100,000 population between 1976 and 2018 was 1.0 (95% CI 0.8-1.3) and was highest in patients ages 30-39 years. Between the 1976-1989 and 2000-2018 time periods, overall incidence of LN increased from 0.7 to 1.3 per 100,000, but this was not statistically significant. Estimated LN prevalence increased from 16.8 per 100,000 in 1985 to 21.2 per 100,000 in 2015. Patients with LN had an SMR of 6.33 (95% CI 3.81-9.89), with no improvement in the mortality gap in the last 4 decades. At 10 years, survival was 70%, and 13% of LN patients had ESRD. The incidence and prevalence of LN in this area increased in the last 4 decades. LN patients have poor outcomes, with high rates of ESRD and mortality rates 6 times that of the general population.

Use of renin angiotensin aldosterone system inhibitors in children with lupus and time to glucocorticoid discontinuation

There is little data to inform use of renin angiotensin aldosterone system (RAAS) inhibitors in pediatric patients with systemic lupus erythematosus (SLE). Here, we sought to characterize RAAS inhibitor use in pediatric SLE and determine whether early RAAS inhibitor initiation among children with incident lupus nephritis is associated with decreased duration of chronic glucocorticoid exposure. A retrospective cohort study was performed of children (ages 5-18) with SLE and/or lupus nephritis in the Truven MarketScan™ Medicaid and Commercial databases (2013-2018) and estimated RAAS inhibitor use. Among incident nephritis cases, we used competing risk hazard models with inverse probability of treatment weighting to estimate the association between RAAS inhibitor initiation less than 180 days after diagnosis and time to glucocorticoid discontinuation with kidney failure as a competing event. Among 592 children with nephritis and 1407 children with non-kidney SLE, 67% and 15% ever received RAAS inhibitors, respectively. Median duration of RAAS inhibitor use among 323 incident users was 14 and 9 months in children with and without nephritis, respectively. Medicaid enrollment was independently associated with greater likelihood of RAAS inhibitor use, irrespective of nephritis. Among 158 incident nephritis cases, early RAAS inhibitor initiation was significantly associated with a faster rate of glucocorticoid discontinuation (adjusted sub-distribution hazard ratio 1.81, 95% confidence interval [1.09 - 3.00]). Thus, early initiation of RAAS inhibitors may have a role in children newly diagnosed with lupus nephritis; not only those with refractory proteinuria after induction therapy. Hence, integrated health systems data could be leveraged to confirm these findings and optimize adjunctive therapies in pediatric lupus.

Association of Renal Arteriosclerosis With Atherosclerotic Cardiovascular Disease Risk in Lupus Nephritis.

Lupus nephritis (LN) predicts a 9-fold higher atherosclerosis cardiovascular disease (ASCVD) risk, highlighting the urgent need to target ASCVD prevention. Studies in IgA nephropathy reported that severe renal arteriosclerosis (r-ASCL) in diagnostic biopsies strongly predicted ASCVD risk. We recently found that 50% of LN pathology reports overlooked r-ASCL reporting, which could explain prior negative LN ASCVD risk studies. The present study was undertaken to examine associations between a composite of reported and overread r-ASCL and ASCVD events in LN. Data were abstracted from all LN patients who underwent diagnostic biopsy between 1994 and 2017, including demographic information, ASCVD risk factors, and pathology reports at the time of LN diagnosis. We manually validated all incident ASCVD events. We overread 25% of the biopsies to grade r-ASCL using the Banff criteria. We supplemented the overread r-ASCL grade, when available, to determine the composite of reported and overread r-ASCL grade. Among 189 incident LN patients, 78% were female, 73% White, and the median age was 25 years. Overall, 31% had any reported r-ASCL, and 7% had moderate-to-severe r-ASCL. After incorporating systematically re-examined r-ASCL grade, the prevalence of any and moderate-to-severe r-ASCL increased to 39% and 12%, respectively. We found 22 incident ASCVD events over 11 years of follow-up. Using a composite of reported and overread r-ASCL grade, we found that severe r-ASCL in diagnostic LN biopsies was associated with 9-fold higher odds of ASCVD. Severe r-ASCL can predict ASCVD in LN; therefore, larger studies are required to systematically report r-ASCL and examine ASCVD associations.

Changing trends in presentation and indications of biopsy in lupus nephritis: data from the Spanish Registry of Glomerulonephritis.

ABSTRACTBackgroundWith the ageing population and changes in the indications of diagnostic and protocol biopsies in systemic lupus erythematosus in recent years, an impact on the incidence and presentation of lupus nephritis (LN) is expected. The aim of this study was to analyse the epidemiological changes regarding clinical and histological presentation of LN in kidney biopsies performed from 1994 to 2019 included in the Spanish Registry of Glomerulonephritis.MethodsWe analysed data from 28 791 kidney biopsies from 130 Spanish hospitals comparing demographic, clinical and histological data. We divided the cohort according to the age of onset of LN into pediatric onset (<18 years), adult onset (18–50 years) and late onset (>50 years).ResultsThe incidence of LN has decreased from 9.6% of all kidney biopsies in the period 1994–2013 to 7% in the last quarter of the observation period (2014–2019) (P < 0.001), despite an increase in the proportion of patients with LN that underwent repeat biopsies (16.6–24%; P < 0.001). The age of onset of LN has increased from 32 ± 14 to 38 ± 14 years (P < 0.001), with an increase in the proportion of late-onset LN (from 13% to 22% of incident LN; P < 0.001). There were no differences in the distribution of histological features at presentation over the study period. Patients with late-onset LN showed fewer gender differences, had lower GFR and presented with less-proliferative forms of LN compared with early-onset LN.ConclusionsThe frequency of biopsy-proven LN has been decreasing in recent years, despite an increasing number of repeat biopsies. Late-onset LN is increasing, presenting with worse kidney function but fewer proliferative lesions compared with younger-onset LN.

High Burden of Premature Arteriosclerosis on Renal Biopsy Results in Incident Lupus Nephritis

Cardiovascular disease (CVD) is accelerated in patients with systemic lupus erythematosus and lupus nephritis (LN). Despite the literature suggesting that renal arteriosclerosis predicts CVD in other glomerulonephritis diseases, arteriosclerosis grading and reporting might be particularly overlooked in LN biopsies. Our objective was to examine the burden of renal arteriosclerosis in LN and to assess whether arteriosclerosis is underreported in LN biopsies. We identified all patients with LN undergoing kidney biopsy between 1994 and 2017 at an academic center. We interpreted LN biopsy reports to classify the Banff categories of absent, mild, moderate, or severe renal arteriosclerosis. The prevalence of renal arteriosclerosis was compared with the prevalence published for age-matched healthy peers, and predictors of arteriosclerosis were examined. We overread biopsies for Banff renal arteriosclerosis grading and compared to pathology reports. Among 189 incident patients with LN, renal arteriosclerosis prevalence was 2 decades earlier compared to their healthy peers, affecting 40% of patients ages 31-39 years with LN compared to 44% of healthy peers ages 50-59 years. A multivariable analysis showed a 3-fold higher odds of renal arteriosclerosis in patients ages ≥30 years with LN. LN chronicity on biopsy results predicted a 4-fold higher odds of renal arteriosclerosis. The overreads determined that 50% of standard LN biopsy reports missed reporting the presence or absence of renal arteriosclerosis. Renal arteriosclerosis is accelerated by 2 decades in patients with LN compared to their healthy peers and is overlooked by pathologists in half of the routine biopsy reports. We propose incorporating Banff renal arteriosclerosis grading in all LN biopsy reports.

A longitudinal multiethnic study of biomarkers in systemic lupus erythematosus: Launching the GLADEL 2.0 Study Group.

Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of "Lupus Investigators" in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.

Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis.

Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis. Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls. Ex vivo NET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques. Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3-C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant of DNASE1L3. Ex vivo NET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases. Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rare DNase1L3 mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered at ClinicalTrials.gov, study number NCT02403115).

Clinical and Serological Associations with the Development of Incident Proteinuria in Danish Patients with Systemic Lupus Erythematosus.

In a longitudinal cohort study, we investigated whether clinical and serological manifestations at the time of classification of systemic lupus erythematosus (SLE) were predictive of subsequent development of incident proteinuria as a biomarker of incident lupus nephritis. Patients fulfilling SLE classification criteria but having no proteinuria prior to or at the time of classification were included. Data on SLE manifestations, vital status, criteria-related autoantibodies, and SLE-associated medications were collected during clinical visits and supplemented by chart review. HR were calculated by Cox regression analyses. Out of 850 patients with SLE, 604 had not developed proteinuria at the time of SLE classification. Of these 604 patients, 184 (30%) developed incident proteinuria following SLE classification. The patients had a median followup of 11 years and 7 months. Younger age and history of psychosis at the time of classification were associated with development of incident proteinuria, just as were lymphopenia (HR 1.49, 95% CI 1.08-2.06), anti-dsDNA (HR 1.38, 95% CI 1.01-1.87), and a high number of autoantibodies (HR 1.26, 95% CI 1.06-1.48). The risk of incident proteinuria after onset of SLE was increased by the presence of lymphopenia, anti-dsDNA antibodies, psychosis, younger age, and a high number of autoantibodies at onset.

Sex Differences in Health Care Utilization, End-Stage RenalDisease, and Mortality Among MedicaidBeneficiaries With Incident Lupus Nephritis.

While systemic lupus erythematosus and lupus nephritis (LN) disproportionately affect females, previous studies suggest that males may experience poorer outcomes. We undertook this study to investigate sex differences in health care utilization, end-stage renal disease (ESRD), and mortality among patients with LN receiving Medicaid, public insurance for low-income individuals. Within the Medicaid Analytic eXtract (MAX) from 29 states (from 2000 to 2010), we used billing claims to identify individuals ages 5-65 years with incident LN (positive predictive value 80%). MAX data were linked to the US Renal Data System to determine ESRD and to Social Security Death Index files to determine death. We estimated adjusted incidence rate ratios (IRRs) by sex for health care utilization using Poisson regression, and we used multivariable proportional hazards models to compare risks of ESRD and death by sex. Of 2,750 patients with incident LN, 283 (10%) were male. The mean ± SD follow-up period for both sexes was 3.1 ± 2.3 years. The mean ± SD age was 29.6 ± 13.9 years among females and 24.7 ± 14.1 years among males (P < 0.01). Males had fewer outpatient visits (IRR 0.88 [95% confidence interval (95% CI) 0.80-0.97]) and fewer emergency department visits (IRR 0.75 [95% CI 0.63-0.90]). The 5-year cumulative incidence of ESRD was 22.3% in males and 21.2% in females. The 5-year cumulative incidence of death was 9.4% in males and 9.8% in females. Comparing males to females, there were no sex differences in ESRD (subdistribution hazard ratio [HR] 1.05 [95% CI 0.76-1.45]) or death (HR 0.81 [95% CI 0.47-1.35]). In this cohort of patients with incident LN, ESRD and mortality were extremely high overall but were not increased among males compared to females. In this vulnerable population, biologic and health care utilization differences by sex may not significantly affect outcomes.

Quality of Care for Incident Lupus Nephritis Among Medicaid Beneficiaries in the United States

We investigated the quality of care and factors associated with variations in care among a national cohort of Medicaid enrollees with incident lupus nephritis. Using Medicaid Analytic eXtract files from 47 US states and the District of Columbia for 2000-2006, we identified a cohort of individuals with incident lupus nephritis. We assessed performance on 3 measures of health care quality: receipt of immunosuppressive, renal-protective antihypertensive, and antimalarial medications. We examined performance on these measures over 1 year and applied multivariable logistic regression models to understand whether sociodemographic, geographic, or health care access factors were associated with higher performance on quality measures. We identified 1,711 Medicaid enrollees with incident lupus nephritis. Performance on quality measures was low at 90 days (21.9% for immunosuppressive therapy, 44.0% for renal protection, and 36.4% for antimalarials) but increased by 1 year (33.7%, 56.4%, and 45.8%, respectively). Younger individuals, African Americans, and Hispanics were more likely to receive immunosuppressive therapy and hydroxychloroquine. Younger individuals were less likely to receive renal-protective antihypertensive medications. We found significant geographic variation in performance, with patients in the Northeast receiving higher quality of care compared to other regions. Poor access to health care, as assessed by having a greater number of treat-and-release emergency department visits compared to ambulatory encounters, was associated with lower receipt of recommended treatment. These nationwide data suggest low overall quality of care and potential delays in care for Medicaid enrollees with incident lupus nephritis. Significant regional differences also suggest room for quality improvement.

SAT0186 Trends and correlates of erythropoiesis-stimulating agent use among patients with lupus nephritis reaching end-stage renal disease

BackgroundApproximately 20% of lupus nephritis (LN) patients develop end-stage renal disease (ESRD) within 10 years. As LN progresses, anemia is common. Little is known, however, about utilization patterns of erythropoiesis-stimulating...

Erythropoiesis-stimulating Agent Use among Patients with Lupus Nephritis Approaching End-stage Renal Disease

ObjectivesLittle is known about erythropoiesis-stimulating agents (ESAs) utilization among lupus nephritis (LN) patients with incipient ESRD. We aimed to identify sociodemographic and clinical factors associated with ESA use among incident LN ESRD patients.MethodsAmong all individuals age ≥18 with incident ESRD from 1995-2008 in the U.S. Renal Data System (USRDS), we identified those with systemic lupus erythematosus (ICD-9 code 710.0) as the cause of ESRD. ESA use at ESRD onset was ascertained from the Medical Evidence Report. Year of onset, age, sex, race/ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered potentially associated with ESA use in multivariable-adjusted logistic regression analyses.ResultsWe identified 12,533 individuals with incident LN ESRD (1% of entire population). Of those, 4,288 (34%) received an ESA preceding ESRD. In multivariable-adjusted models, ESA users had higher serum albumin and hemoglobin concentrations, were more likely to be women, and to live in the Northeast. Conversely, Medicaid beneficiaries, the uninsured, unemployed, African Americans, Hispanics, and those with IV drug use, congestive heart failure and obesity had lower ESA use.ConclusionAmong all U.S. patients and those with LN who developed ESRD, approximately one third received ESAs. Patient sex, race, age, medical insurance, residential region and clinical factors were significantly associated with ESA therapy. While there are no guidelines for ESA use in LN patients approaching ESRD, there has been wide sociodemographic variation, raising questions about ESA prescription practices.

Usual source of care and geographic region are largest predictors of healthcare quality for incident lupus nephritis in US Medicaid recipients

Usual source of care and geographic region are largest predictors of healthcare quality for incident lupus nephritis in US Medicaid recipients

Variation in initial kidney replacement therapy for end‐stage renal disease due to lupus nephritis in the United States

Little is known about the patterns of use of initial kidney replacement therapies among patients with lupus nephritis (LN) end-stage renal disease (ESRD). We aimed to identify sociodemographic and clinical factors associated with variation in initial kidney replacement therapies among LN ESRD patients. Patients with incident LN ESRD (1995-2006) were identified in the US Renal Data System. Age, sex, race, ethnicity, medical insurance, employment status, residential region, clinical factors, and comorbidities were considered as potential predictors of ESRD treatment choice, i.e., peritoneal dialysis (PD), hemodialysis (HD), or preemptive kidney transplantation in age-adjusted and multivariable-adjusted logistic regression analyses. Of the 11,317 individuals with incident LN ESRD, 82.0% initiated HD, 12.2% initiated PD, and 2.8% underwent preemptive kidney transplantation. Receiving initial PD was significantly associated with earlier calendar year, female sex, higher albumin and hemoglobin levels, and lower serum creatinine levels. African Americans (versus whites), Medicaid beneficiaries and those with no health insurance (versus private insurance), and those unemployed (versus employed) had significantly reduced PD initiation. Comorbidities including congestive heart failure, peripheral vascular disease, and the inability to ambulate were also associated with decreased PD. Many sociodemographic and clinical factors favoring PD were associated with preemptive kidney transplant (versus dialysis) as well. Few patients with LN ESRD receive initial PD or preemptive kidney transplantation. Race, ethnicity, employment, and medical insurance type are strongly associated with initial kidney replacement therapy choice. Future studies need to investigate the appropriateness of sociodemographic and clinical variation and the comparative effectiveness of kidney replacement therapies for LN ESRD.

Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006.

This study was undertaken to investigate whether recent advances in lupus nephritis treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to lupus nephritis, or in the characteristics, treatments, and outcomes of patients with lupus nephritis ESRD. Patients with incident lupus nephritis ESRD (1995-2006) were identified in the US Renal Data System. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses. We identified 12,344 incident cases of lupus nephritis ESRD. Mean age at ESRD onset was 41 years; 81.6% of the patients were women and 49.5% were African American. SIRs for lupus nephritis ESRD among those who were ages 5-39 years, African American, or lived in the southeastern US increased significantly from 1995 to 2006. Increases in body mass index and in the prevalence of both diabetes mellitus and hypertension were detected. Mean serum hemoglobin level at ESRD onset increased, while that of serum creatinine decreased over time. More patients received hemodialysis and fewer received peritoneal dialysis. There was a slight increase in the frequency of preemptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first 3 years of ESRD declined. Mortality did not change over the 12 years of study. Our findings indicate that the characteristics of patients with lupus nephritis ESRD and initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans, and in the South, outcomes did not improve in over a decade of evaluation.